Transforming growth factor β-activated kinase 1 (TAK1, also known as MAP3K7) is an intracellular enzyme that sits at the crossroads of several disease pathways. TAK1 is a member of the mitogen-activated protein kinase kinase kinase (MAPKKK or MAP3K) class of serine/threonine kinases.
TAK1 in Cancer: Transforming growth factor beta (TGF-β) is a multifunctional secreted polypeptide involved in the regulation of cell proliferation, differentiation and survival (related to apoptosis) and is implicated in multiple aspects of tumor pathogenesis. TGF-β receptors act through several intracellular signaling cascades that include the canonical SMAD pathway as well as the non-canonical Rho GTPase and TAK1 signaling pathways. TGF-β can directly promote tumor invasiveness and metastasis in addition to induction of angiogenesis and suppression of lymphocyte and macrophage proliferation and differentiation, thereby suppressing immune surveillance of the developing tumor. Reduction of TGF-β activity may therefore be a promising target of therapeutic strategies to control tumor growth.
TAK1, a key downstream effector of TGF-β, has been implicated in transformation and metastasis of cancer cells as well as in the development of resistance to chemotherapeutic drugs and ionizing radiation. TAK1 is required for TGF-β initiated R-Ras mediated transformation of mammary epithelial cells, a process that is independent of SMAD signaling but requires TAK1 directed activation of p38 and c-Jun N-terminal kinase (JNK) pathways. It has been shown that TAK1 activation is involved in metastasis and bone destruction by breast carcinoma cells, as well as in the metastasis and lung invasion of colon cancer cells. The TAK1-dependent activation of p38, JNK and nuclear factor κB (NF-κB) pathways was central to promoting these cancer phenotypes. Multiple genotoxic anti-cancer drugs and ionizing radiation have been shown to activate NF-κB and thereby protect cancer cells from DNA damage-induced apoptosis. For example, two anticancer drugs, doxorubicin and etoposide, when tested in multiple cancer cell lines, promoted TAK1-mediated DNA-damage response-pathway that involved the downstream activation of NF-κB, p38 and MK2, conferring chemoresistance and promoting cancer cell survival. The role of TAK1, as a potential mediator of the extreme drug resistance displayed by pancreatic cancer, was studied using an orally, bioavailable small molecule inhibitor of TAK1, LYTAK1. Results demonstrated an increased sensitivity of pancreatic cancer cells to chemotherapeutic drugs gemcitabine and oxaliplatin (Melisi, et al. J. Natl. Cancer Inst. 103, 1190-1204 (2011)).
TAK1 in Inflammation and Autoimmune Disease: TAK1 is also a key mediator of pro-inflammatory and stress signals. Cellular activation of TAK1 activity is promoted by pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) as well as by the engagement of T cell, B cell and toll-like receptors. TAK1 activation induces the downstream nuclear translocation of NF-κB and activation of the JNK and p38 pathways that are central to driving inflammatory and immune responses as well as T cell and B cell development, activation and survival.
Protein-based (biologics) and small molecule drugs that block TNF-α (ENBREL, HUMIRA, REMICADE, SIMPONI) or IL-1β (KINERET) signaling or that limit T cell (ORENCIA, TYSABRI) or B cell (RITUXAN) function have been used to treat a number of autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, cryopyrin associated periodic syndromes and inflammatory bowel disease (IBD). The essential role of TAK1 in modulating TNF-α and IL-1β production and signaling and T cell and B cell function make it important in autoimmune chronic inflammatory and autoinflammatory diseases.
TAK1 plays a pivotal role in JNK-mediated activation of metalloproteinase (MMP) gene expression and joint destruction in inflammatory arthritis. In animal models of autoimmune arthritis, the targeted knockdown of TAK1 with small interfering RNA (siRNA) provides disease-modifying benefit, both prophylactically and therapeutically. At the molecular and cellular levels, TAK1 knockdown severely impairs JNK and NF-κB signaling, down-regulated expression of pro-inflammatory mediators and constrains the expansion of IL-17A producing T cells that contribute to the pathogenesis of rheumatoid arthritis and other autoimmune diseases. The immunosuppressive impact of TAK1 deletion has also been studied in an animal model of contact hypersensitivity (CHS), a classic T cell-mediated immune response. Both dendritic cells (innate immunity) and T cells (adaptive immunity) play critical roles in the onset of CHS. By specifically deleting TAK1 in dendritic cells in a mouse model, it was shown that TAK1 is essential in dendritic cell-mediated T cell activation and the development of CHS (Zhao, et al. Cell. Mol. Immunol. 8, 315-324 (2011)).
Compounds useful as protein kinase inhibitors for treatment of proliferative diseases including cancer are reported in WO 2011/133637 (pub. 27 Oct. 2011). A compound described therein is 4-((5-(6-((4,4-difluorocyclohexyl)amino)-2-fluoronicotinoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-2-one.
Compounds useful as epidermal growth factor receptor (EGFR) inhibitors for treatment of proliferative diseases including cancer are reported in WO 2010/129053 (pub. 11 Nov. 2010). A compound described therein is N-(3-((5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide.
Compounds useful as Raf inhibitors for treatment of proliferative diseases including cancer are reported in WO 2011/063159 (pub. 26 May 2011). A compound described therein is N-(2,4-difluoro-3-(4-isobutoxy-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-4-(trifluoromethyl)benzenesulfonamide.
Compounds useful as PDK1 inhibitors for cancer treatment are reported in WO 2010/003133 (pub. 7 Jan. 2012). A compound described therein is 4-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-amine.
S-(4-substituted-5-cyano-2-methyl-7H-pyrrolo[2,3-d]-pyrimidin-6-yl)thioacetic acid derivatives are reported as intermediate compounds for the syntheses of S-(5-carbamoyl-2-methyl-4-oxo-3,4-dihydropyrrolo[2,3-d]pyrimidin-6-yl) thioacetic acid ester product compounds (A. Ebenereth, et al, Pharmazie (1992), 47(8), 571-3). These amido-derivative product compounds are described as proving to be of particular interest as chemotherapeutic agents.